The virtual screening of compounds in databases is an important tool in modern drug design. Traditionally, two-dimensional or pharmacophore-based methods, which are very fast but have only limited accuracy, have been used for this purpose. (See, for example, H. Matter et al., in Combinatorial Organic Chemistry, John Wiley & Sons, New York, N.Y., 1999; C. Humblet et al., Annual Reports in Medicinal Chemistry, vol. 28, Chapter VI, Topics in Drug Design and Discovery, Academic Press, London, pp. 275-284, 1993; P. Willet, J. Mol. Recognition, vol. 8, p. 290, 1995; and R. D. Brown et al., J. Chem. Inf. Comput. Sci., vol. 36, p. 572, 1996.)
Three-dimensional molecular superposition methods have been successfully utilized to determine binding geometries relative to a reference molecule. (See, for example, G. Klebe et al., J. Comput. Aided Mol. Des., vol. 8, p. 751, 1994; S. K. Kearsley, et al., J. Comput. Aided Mol. Des., vol. 8, p. 565, 1994; G. Klebe et al., J. Comput. Aided Mol. Des., vol. 13, p. 35, 1999; C. Lemmen et al., J. Comput. Aided Mol. Des., vol. 11, p. 357, 1997; C. Lemmen, J. Med. Chem., vol. 41, p. 4502, 1998; C. Lemmen et al., J. Comput. Aided Mol. Des., vol. 12, p. 491, 1998; M. D. Miller et al., J. Med. Chem., vol. 42, p. 1505, 1999; J. A. Grant et al., J. Comput. Chem., vol. 17, p. 1653, 1996; C. McMartin et al., J. Comput. Aided Mol. Des., vol. 9, p. 237; and S. Handschuh et al., J. Chem. Inf. Comput. Sci., vol. 38, p. 220, 1998.) These 3-D methods play an important role in 3D-QSAR (Quantitative Structure-Activity Relationships) applications, pharmacophore elucidation, and receptor modeling—situations in which structural data of the target protein is not available. The variety of methodologies used for molecular superposition has recently been extensively reviewed (see Lemmen et al., J. Comput. Aided Mol. Des., vol. 14, p. 215, 2000), and an application of existing superposition methods to virtual database screening has been reported (see C. Lemmen et al., Perspectives in Drug Discovery and Design, vol. 20, p. 43, 2000).
Of course, the use of molecular superposition to determine the binding capability of possible ligands has its limitations. The underlying assumption is that other ligands will have the same overall binding mode as the reference molecule. Also, the bound conformation of the reference molecule has to be known, which is generally true only if crystallographic information about the corresponding protein-ligand complex is available. Therefore, in practical applications, the reference molecule should have a non-flexible structure, or its bound conformation has to be inferred using other methods, e.g., deduced from simultaneous, flexible alignments within a set of ligands that are known to be active. (See, for example, S. K. Kearsley et al., J. Comput. Chem., vol. 11, p. 1187, 1990; R. Diamond, Protein Sci., vol. 1, p. 1279, 1992; J. Mestres et al., J. Mol. Graph., vol. 15, p. 114, 1997; D. A. Cosgrove et al., J. Comput. Aided Mol. Des., vol. 14, p. 573, 2000; P. Labute et al., J. Med. Chem., vol. 44 p. 1483, 2001; and J. E. J. Mills et al., J. Comput. Aided Mol. Des., vol. 15, p. 81, 2001.) The bound conformation of the reference molecule can also be determined from distance constraints obtained in NMR (NOE) experiments (see G. C. K. Roberts, Drug Discovery Today, vol. 5, p. 230, 2000).
A field-based similarity search system and method have been described in which there is no screening of the conformation space, leading to a high computational load (see M. C. Pitman et al., J. Comput. Aided Mol. Des., vol. 15, p. 587, 2001). In this approach, all candidate molecules must first be assembled before they are scored. U.S. Pat. Nos. 5,787,279 and 5,752,019 to Rigoutsos describe other search systems and methods in which the search is based on atom types, and pose-clustering (a particular method of clustering of coordinate systems arbitrarily located and rotated in space) is used to generate alignments (hypotheses).
There is still a need for an accurate, efficient method of performing a database search of molecules that fully accounts for the three-dimensional structure and conformational flexibility of the molecules in the database.